HRP20140213T1 - Indazole and pyrazolopyridine compounds as ccr1 receptor antagonists - Google Patents

Indazole and pyrazolopyridine compounds as ccr1 receptor antagonists Download PDF

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HRP20140213T1
HRP20140213T1 HRP20140213AT HRP20140213T HRP20140213T1 HR P20140213 T1 HRP20140213 T1 HR P20140213T1 HR P20140213A T HRP20140213A T HR P20140213AT HR P20140213 T HRP20140213 T HR P20140213T HR P20140213 T1 HRP20140213 T1 HR P20140213T1
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alkyl
alkoxy
optionally substituted
alkoxycarbonyl
nrcrd
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Brian Nicholas Cook
Daniel Kuzmich
Can Mao
Hossein Razavi
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Boehringer Ingelheim International Gmbh
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Claims (16)

1. Spoj, naznačen time, da ima formulu (I) [image] u kojoj X je dušik ili C-R2; Ar1 je karbocikl, heteroaril ili heterociklil, svaki opcijski supstituiran s jednim do tri Ra; Ar2 karbocikl, heteroaril ili heterociklil, svaki opcijski supstituiran s jednim do tri Rb; Prsten G je karbocikl ili heterociklil, svaki opcijski supstituiran s jednim do dva Rg; R1 je vodik, C1-6 alkil ili C1-6 alkoksi-C1-6 alkil; R2 je vodik ili Ra; Raje C1-6alkil, C3-10 cikloalkil, C1-6 alkoksi, C1-6 alkiltio, C1-6 alkilsulfonil, C1-6 alkoksikarbonil, amino, mono-ili di-C1-6 alkilamino, C3-6 cikloalkilamino, C1-6 alkilaminokarbonil, C1-6 acil, C1-6 acilamino, C1-6 dialkilaminokarbonil, hidroksil, halogen, cijano, nitro, okso, R3-S(O)m-NH-, R3-NH-S(O)m-, aril ili karboksil; Rb je hidroksil, karboksil, halogen, -(CH2)n-CN, -(CH2)n-CO2C1-6alkil, nitro, -SO3H, C1-6 alkil, C2-6 alkenil, C2-6 alkinil, C3-10 cikloalkil, C1-6 alkoksi, C1-6alkilC(O)-, -(CH2)n-NRcRd, R3-S(O)m (CH2)0-1-, R3-S(O)m-NRe-, R3-NRe-S(O)m(CH2)0-1-, -NRf-C(O)-Re, -(CH2)y-C(O)-(CH2)n-NRcRd, heterociklil, aril ili heteroaril, svaki Rb, gdje je to moguće, opcijski je halogeniran ili supstituiran s 1 do 3 od sljedećih: C1-6 alkil, hidroksil, C1-6 acil, C1-6 alkoksikarbonil, C1-6 alkil-S(O)m-, aril ili karboksil; svaki Rc, Rdje neovisno vodik, C1-6 alkil, C1-6 acil, C3-10 cikloalkil, C1-6 alkoksi, hidroksi-C1-6 alkil, cijano-C1-6 alkil, C1-6 alkil-C1-6 alkoksi, C1-6 alkilsulfonil, C1-6 alkoksikarbonil-C0-3alkil, C1-6 akoksikarbonil-C3-10cikloalkil, -(CH2)n-C(O)-NReRf ili -(CH2)n-NReRf; svaki Re, Rfje neovisno vodik, C1-6 alkil, C3-10 cikloalkil, C1-6 alkoksi, C1-6 alkoksi-C1-6 alkil, mono-ili di-C1-6 alkilamino-C1-6alkil, hidroksi-C1-6 alkil ili C1-6 acil; Rgje C1-6 alkil, gdje je C1-6 alkil opcijski djelomično ili potpuno halogeniran, C2-6 alkenil, karbocikl, C1-6 alkoksi, karbociklil-C1-6 alkoksi, karbociklil-C1-6 alkil, hidroksi-C1-6 alkil, hidroksil, -(CH2)n-CO2C1-6 alkil ili okso; R3je vodik, C1-6 alkil, C3-6cikloalkil, heterociklil(CH2)0-1, mono-ili di-C1-6 alkilamino, mono-ili di-C1-6alkilamino(CH2)2-3N(Re)-, aril ili heteroaril, svaki opcijski supstituiran s 1 do 3 od sljedećih: C1-6 alkil, C3-6cikloalkil, C1-6 alkoksi, halogen, hidroksil, okso, karboksil, -C(O)NReRf, amino, mono-ili di-C1-6 alkilamino, C1-6 alkoksikarbonil ili C1-6 acilamino; svaki n, y je neovisno 0-3; svaki m je neovisno 0-2; ili njegova farmaceutski prihvatljiva sol. 1. A compound characterized by having the formula (I) [image] where X is nitrogen or C-R2; Ar 1 is carbocycle, heteroaryl or heterocyclyl, each optionally substituted with one to three Ra; Ar 2 carbocycle, heteroaryl or heterocyclyl, each optionally substituted with one to three Rb; Ring G is carbocycle or heterocyclyl, each optionally substituted with one to two Rg; R 1 is hydrogen, C 1-6 alkyl or C 1-6 alkoxy-C 1-6 alkyl; R 2 is hydrogen or Ra; Preferably C1-6alkyl, C3-10 cycloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylsulfonyl, C1-6 alkoxycarbonyl, amino, mono-or di-C1-6 alkylamino, C3-6 cycloalkylamino, C1-6 alkylaminocarbonyl, C1-6 acyl, C1-6 acylamino, C1-6 dialkylaminocarbonyl, hydroxyl, halogen, cyano, nitro, oxo, R3-S(O)m-NH-, R3-NH-S(O)m-, aryl or carboxyl; Rb is hydroxyl, carboxyl, halogen, -(CH2)n-CN, -(CH2)n-CO2C1-6alkyl, nitro, -SO3H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl , C1-6 Alkoxy, C1-6alkylC(O)-, -(CH2)n-NRcRd, R3-S(O)m (CH2)0-1-, R3-S(O)m-NRe-, R3- NRe-S(O)m(CH2)0-1-, -NRf-C(O)-Re, -(CH2)y-C(O)-(CH2)n-NRcRd, heterocyclyl, aryl or heteroaryl, each Rb, where possible, is optionally halogenated or substituted with 1 to 3 of the following: C1-6 alkyl, hydroxyl, C1-6 acyl, C1-6 alkoxycarbonyl, C1-6 alkyl-S(O)m-, aryl or carboxyl; each Rc, Rd is independently hydrogen, C1-6 alkyl, C1-6 acyl, C3-10 cycloalkyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, cyano-C1-6 alkyl, C1-6 alkyl-C1-6 alkoxy . each R e , R f is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, mono- or di-C 1-6 alkylamino-C 1-6 alkyl, hydroxy-C 1- 6 alkyl or C1-6 acyl; Rg is C1-6 alkyl, where C1-6 alkyl is optionally partially or fully halogenated, C2-6 alkenyl, carbocycle, C1-6 alkoxy, carbocyclyl-C1-6 alkoxy, carbocyclyl-C1-6 alkyl, hydroxy-C1-6 alkyl , hydroxyl, -(CH2)n-CO2C1-6 alkyl or oxo; R3 is hydrogen, C1-6 alkyl, C3-6 cycloalkyl, heterocyclyl(CH2)0-1, mono-or di-C1-6 alkylamino, mono-or di-C1-6 alkylamino(CH2)2-3N(Re)-, aryl or heteroaryl, each optionally substituted with 1 to 3 of the following: C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, halogen, hydroxyl, oxo, carboxyl, -C(O)NReRf, amino, mono-or di-C1 -6 alkylamino, C1-6 alkoxycarbonyl or C1-6 acylamino; each n, y is independently 0-3; each m is independently 0-2; or a pharmaceutically acceptable salt thereof. 2. Spoj prema zahtjevu 1, naznačen time, da Prsten G je karbocikl opcijski supstituiran s jednim do dva Rg , ili njegova farmaceutski prihvatljiva sol. 2. A compound according to claim 1, characterized in that Ring G is a carbocycle optionally substituted with one to two Rg, or a pharmaceutically acceptable salt thereof. 3. Spoj prema zahtjevu 2, naznačen time, da X je dušik; Ar1 je karbocikl opcijski supstituiran s jednim do tri Ra; Ar2 je karbocikl ili heteroaril, svaki opcijski supstituiran s jednim do tri Rb; R1 je vodik; Raje C1-3alkil, C1-3 alkoksi, di-C1-6 alkilamino, metilsulfonil, halogen ili cijano; Rb je hidroksil, karboksil, halogen, -(CH2)n-CN, -(CH2)n-CO2C1-6alkil, nitro, -SO3H, C1-6 alkil, C2-6 alkenil, C2-6 alkinil, C3-10cikloalkil, C1-6alkoksi, C1-6alkilC(O)-, -(CH2)n-NRcRd, R3-S(O)m(CH2)0-1-, R3-S(O)m-NRe-, R3-NRe-S(O)m(CH2)0-1-, -NRf-C(O)-Re, -(CH2)y-C(O)-(CH2)n-NRCRd, heterociklil, aril ili heteroaril, svaki Rb, gdje je to moguće, opcijski je halogeniran ili supstituiran s 1 do 3 od sljedećih: C1-6 alkil, C1-6 acil, C1-6 alkoksikarbonil, C1-6 alkil-S(O)m-, aril ili karboksil; R3 vodik, C1-6 alkil, C3-6cikloalkil, heterociklil(CH2)0-1, mono-ili di-C1-6 alkilamino, mono-ili di- C1-6 alkilamino(CH2)2-3N(C1-6alkil)-, aril ili heteroaril, svaki opcijski supstituiran s 1 do 2 od sljedećih: C1-6 alkil, C3-6cikloalkil, C1-6 alkoksi, halogen, hidroksil, okso, karboksil, -C(O)NReRf, amino, mono-ili di-C1-6 alkilamino, C1-6 alkoksikarbonil ili C1-6 acilamino, ili njegova farmaceutski prihvatljiva sol.3. Compound according to claim 2, characterized in that X is nitrogen; Ar 1 is a carbocycle optionally substituted with one to three Ra; Ar2 is carbocycle or heteroaryl, each optionally substituted with one to three Rb; R 1 is hydrogen; Preferably C1-3alkyl, C1-3 alkoxy, di-C1-6 alkylamino, methylsulfonyl, halogen or cyano; Rb is hydroxyl, carboxyl, halogen, -(CH2)n-CN, -(CH2)n-CO2C1-6alkyl, nitro, -SO3H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10cycloalkyl, C1-6Alkoxy, C1-6alkylC(O)-, -(CH2)n-NRcRd, R3-S(O)m(CH2)0-1-, R3-S(O)m-NRe-, R3-NRe- S(O)m(CH2)0-1-, -NRf-C(O)-Re, -(CH2)y-C(O)-(CH2)n-NRCRd, heterocyclyl, aryl or heteroaryl, each Rb, where optionally, it is optionally halogenated or substituted with 1 to 3 of the following: C1-6 alkyl, C1-6 acyl, C1-6 alkoxycarbonyl, C1-6 alkyl-S(O)m-, aryl or carboxyl; R3 hydrogen, C1-6 alkyl, C3-6cycloalkyl, heterocyclyl(CH2)0-1, mono-or di-C1-6 alkylamino, mono-or di-C1-6 alkylamino(CH2)2-3N(C1-6alkyl) -, aryl or heteroaryl, each optionally substituted with 1 to 2 of the following: C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, halogen, hydroxyl, oxo, carboxyl, -C(O)NReRf, amino, mono-or di-C1-6 alkylamino, C1-6 alkoxycarbonyl or C1-6 acylamino, or a pharmaceutically acceptable salt thereof. 4. Spoj prema zahtjevu 3, naznačen time, da Ar1je fenil supstituiran s jednim do dva Ra; Ar2 je fenil, tiadiazolil, oksadiazolil, pirimidinil, furanil, tiazolil ili piridil, svaki opcijski supstituiran s jednim do dva Rb; Prsten G je ciklopropil ili ciklobutil; Ra je halogen; Rb je hidroksil, karboksil, halogen, -CF3, -CN, -SO3H, C1-3 alkil, C3-6 cikloalkil, C1-3 alkoksi, -(CH2)n-CO2C1-3 alkil, -(CH2)n-NRCRd, R3-S(O)m(CH2)0-1-, R3-S(O)2 -NRe-, R3-NRe-S(O)2(CH2)0-1-, -NRf-C(O)-Re, -(CH2)y-C(O)-NRCRd ili morfolinil; svaki Rc, Rd je neovisno vodik, C1-3 alkil, C1-3 acil, cijano-C1-3 alkil, C1-3 alkoksikarbonil-C0-3 alkil, C1-3 alkoksikarbonil-C3-6 cikloalkil ili -(CH2)n-C(O)- NReRf; svaki Re, Rf je neovisno vodik ili C1-3 alkil; R3 je vodik ili C1-6alkil, svaki opcijski supstituiran s jednim do dva C1-6 alkoksi ili okso, ili njegova farmaceutski prihvatljiva sol.4. Compound according to claim 3, characterized in that Ar 1 is phenyl substituted with one to two Ra; Ar 2 is phenyl, thiadiazolyl, oxadiazolyl, pyrimidinyl, furanyl, thiazolyl or pyridyl, each optionally substituted with one to two Rb; Ring G is cyclopropyl or cyclobutyl; Ra is halogen; Rb is hydroxyl, carboxyl, halogen, -CF3, -CN, -SO3H, C1-3 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, -(CH2)n-CO2C1-3 alkyl, -(CH2)n-NRCRd , R3-S(O)m(CH2)0-1-, R3-S(O)2 -NRe-, R3-NRe-S(O)2(CH2)0-1-, -NRf-C(O )-Re, -(CH2)y-C(O)-NRCRd or morpholinyl; each Rc, Rd is independently hydrogen, C1-3 alkyl, C1-3 acyl, cyano-C1-3 alkyl, C1-3 alkoxycarbonyl-C0-3 alkyl, C1-3 alkoxycarbonyl-C3-6 cycloalkyl or -(CH2)n-C (O)-NReRf; each R e , R f is independently hydrogen or C 1-3 alkyl; R 3 is hydrogen or C 1-6 alkyl, each optionally substituted with one to two C 1-6 alkoxy or oxo, or a pharmaceutically acceptable salt thereof. 5. Spoj prema zahtjevu 4, naznačen time, da Prsten G je ciklopropil; Ra je –F ili -Cl; Rb je -CH3, karboksil, -F, -Cl, -Br, -I, -CF3, ciklopropil, -OCH3, -CO2Me-NRCRd, -CH2-NRCRd, R3-S(O)m-, R3-S(O)2-NRe-, R3-NRe-S(O)2-, -NRf-C(O)-Re, -C(O)NRCRd ili morfolinil; svaki Rc, Rd je neovisno vodik, -CH3, -C(O)CH3, -CH2CN, C1-4 alkoksikarbonil, metoksikarbonil-C1-2alkil-, metoksikarbonil-C3cikloalkil-, ili -(CH2)-C(O)-NReRf; svaki Rc, Rf je neovisno vodik ili -CH3; R3 je vodik ili C1-4 alkil, svaki opcijski supstituiran s jednim do dva -OCH3 ili okso, ili njegova farmaceutski prihvatljiva sol.5. Compound according to claim 4, characterized in that Ring G is cyclopropyl; Ra is -F or -Cl; Rb is -CH3, carboxyl, -F, -Cl, -Br, -I, -CF3, cyclopropyl, -OCH3, -CO2Me-NRCRd, -CH2-NRCRd, R3-S(O)m-, R3-S( O)2-NRe-, R3-NRe-S(O)2-, -NRf-C(O)-Re, -C(O)NRCRd or morpholinyl; each Rc, Rd is independently hydrogen, -CH3, -C(O)CH3, -CH2CN, C1-4 alkoxycarbonyl, methoxycarbonyl-C1-2alkyl-, methoxycarbonyl-C3cycloalkyl-, or -(CH2)-C(O)-NReRf ; each R c , R f is independently hydrogen or -CH 3 ; R 3 is hydrogen or C 1-4 alkyl, each optionally substituted with one to two -OCH 3 or oxo, or a pharmaceutically acceptable salt thereof. 6. Spoj prema zahtjevu 1, naznačen time, da X je C-R2; Ar1 je karbocikl opcijski supstituiran s jednim do tri Ra; Ar2 je karbocikl ili heteroaril svaki opcijski supstituiran s jednim do tri Rb; Prsten G je karbocikl opcijski supstituiran s jednim do dva Rg; R1 je vodik; R2 je vodik ili Ra; Ra je C1-3alkil, C1-3 alkoksi, di-C1-6 alkilamino, metilsulfonil, halogen ili cijano; Rb je hidroksil, karboksil, halogen, -(CH2)n-CN, -(CH2)n-CO2C1-6alkil, nitro, -SO3H, C1-6 alkil, C2-6 alkenil, C2-6 alkinil, C3-10cikloalkil, C1-6alkoksi, C1-6alkilC(O)-, -(CH2)n-NRCRd, R3-S(O)m(CH2)0-1-, R3-S(O)m-NRe-, R3-NRe-S(O)m(CH2)0-1-, -NRf-C(O)-Re, -(CH2)y-C(O)-(CH2)n-NRCRd, heterociklil, aril ili heteroaril, svaki Rb, gdje je to moguće, opcijski je halogeniran ili supstituiran s 1 do 3 od sljedećih: C1-6 alkil, C1-6 acil, C1-6 alkoksikarbonil, C1-6 alkil-S(O)m-, aril ili karboksil; svaki Rc, Rd je neovisno vodik, C1-6 alkil, C1-6 acil, C3-10 cikloalkil, C1-6 alkoksi, hidroksi-C1-6 alkil, cijanoC1-6 alkil, C1-6 alkil-C1-6 alkoksi, C1-6 alkilsulfonil, C1-6 alkoksikarbonil-C0-3 alkil, C1-6 alkoksikarbonil-C3-10 cikloalkil, -(CH2)n-C(O)-NReRf ili -(CH2)n-NReRf; svaki Re, Rf je neovisno vodik, C1-6 alkil, C3-10 cikloalkil, C1-6 alkoksi, C1-6 alkoksi-C1-6 alkil, mono-ili di-C1-6 alkilamino-C1-6 alkil, hidroksi-C1-6 alkil ili C1-6 acil; R3 je vodik, C1-6 alkil, C3-6 cikloalkil, heterociklil(CH2)0-1, mono-ili di-C1-6 alkilamino, mono-ili di-C1-6 alkilamino(CH2)2-3N(C1-6 alkil)-, aril ili heteroaril, svaki opcijski supstituiran s 1 do 2 od sljedećih: C1-6 alkil, C3-6 cikloalkil, C1-6 alkoksi, halogen, hidroksil, okso, karboksil, -C(O)NReRf, amino, mono-ili di-C1-6 alkilamino, C1-6 alkoksikarbonil ili C1-6 acilamino, ili njegova farmaceutski prihvatljiva sol.6. Compound according to claim 1, characterized in that X is C-R 2 ; Ar 1 is a carbocycle optionally substituted with one to three Ra; Ar2 is a carbocycle or heteroaryl each optionally substituted with one to three Rb; Ring G is a carbocycle optionally substituted with one to two Rg; R 1 is hydrogen; R 2 is hydrogen or Ra; Ra is C 1-3 alkyl, C 1-3 alkoxy, di-C 1-6 alkylamino, methylsulfonyl, halogen or cyano; Rb is hydroxyl, carboxyl, halogen, -(CH2)n-CN, -(CH2)n-CO2C1-6alkyl, nitro, -SO3H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10cycloalkyl, C1-6Alkoxy, C1-6alkylC(O)-, -(CH2)n-NRCRd, R3-S(O)m(CH2)0-1-, R3-S(O)m-NRe-, R3-NRe- S(O)m(CH2)0-1-, -NRf-C(O)-Re, -(CH2)y-C(O)-(CH2)n-NRCRd, heterocyclyl, aryl or heteroaryl, each Rb, where optionally halogenated or substituted with 1 to 3 of the following: C1-6 alkyl, C1-6 acyl, C1-6 alkoxycarbonyl, C1-6 alkyl-S(O)m-, aryl or carboxyl; each Rc, Rd is independently hydrogen, C1-6 alkyl, C1-6 acyl, C3-10 cycloalkyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, cyanoC1-6 alkyl, C1-6 alkyl-C1-6 alkoxy, C1-6 alkylsulfonyl, C1-6 Alkoxycarbonyl-C0-3 alkyl, C1-6 Alkoxycarbonyl-C3-10 cycloalkyl, -(CH2)n-C(O)-NReRf or -(CH2)n-NReRf; each Re, Rf is independently hydrogen, C1-6 alkyl, C3-10 cycloalkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, mono- or di-C1-6 alkylamino-C1-6 alkyl, hydroxy- C1-6 alkyl or C1-6 acyl; R3 is hydrogen, C1-6 alkyl, C3-6 cycloalkyl, heterocyclyl(CH2)0-1, mono-or di-C1-6 alkylamino, mono-or di-C1-6 alkylamino(CH2)2-3N(C1- 6 alkyl)-, aryl or heteroaryl, each optionally substituted with 1 to 2 of the following: C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, halogen, hydroxyl, oxo, carboxyl, -C(O)NReRf, amino , mono-or di-C1-6 alkylamino, C1-6 alkoxycarbonyl or C1-6 acylamino, or a pharmaceutically acceptable salt thereof. 7. Spoj prema zahtjevu 6, naznačen time, da Ar1 je fenil supstituiran s jednim do dva Ra; Ar2 je fenil, tiadiazolil, oksadiazolil, pirimidinil, furanil, tiazolil ili piridil, svaki opcijski supstituiran s jednim do dva Rb; Prsten G je ciklopropil ili ciklobutil; Ra je C1-3alkil, metilsulfonil, halogen ili cijano; Rb je hidroksil, karboksil, halogen, -CF3, -CN, -SO3H, C1-3 alkil, C3-6 cikloalkil, C1-3alkoksi, -(CH2)n-CO2C1-3alkil, -(CH2)n-NRcRd, R3-S(O)m(CH2)0-1-, R3-S(O)2-NRe-, R3-NRe-S(O)2(CH2)0-1-, -NRf-C(O)-Re, -(CH2)y-C(O)-NRcRd ili morfolinil; svaki Rc, Rd je neovisno vodik, C1-3 alkil, C1-3 acil, cijano-C1-3 alkil, C1-3 alkoksikarbonil-C0-3 alkil, C1-3 alkoksikarbonil-C3-6 cikloalkil ili -(CH2)n-C(O)-NReRf; svaki Re, Rf je neovisno vodik ili C1-3 alkil; R3 je vodik ili C1-6 alkil, svaki opcijski supstituiran s jednim do dva C1-6 alkoksi ili okso, ili njegova farmaceutski prihvatljiva sol.7. Compound according to claim 6, characterized in that Ar 1 is phenyl substituted with one to two Ra; Ar 2 is phenyl, thiadiazolyl, oxadiazolyl, pyrimidinyl, furanyl, thiazolyl or pyridyl, each optionally substituted with one to two Rb; Ring G is cyclopropyl or cyclobutyl; R a is C 1-3 alkyl, methylsulfonyl, halogen or cyano; Rb is hydroxyl, carboxyl, halogen, -CF3, -CN, -SO3H, C1-3 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, -(CH2)n-CO2C1-3alkyl, -(CH2)n-NRcRd, R3 -S(O)m(CH2)0-1-, R3-S(O)2-NRe-, R3-NRe-S(O)2(CH2)0-1-, -NRf-C(O)- Re, -(CH2)y-C(O)-NRcRd or morpholinyl; each Rc, Rd is independently hydrogen, C1-3 alkyl, C1-3 acyl, cyano-C1-3 alkyl, C1-3 alkoxycarbonyl-C0-3 alkyl, C1-3 alkoxycarbonyl-C3-6 cycloalkyl or -(CH2)n-C (O)-NReRf; each R e , R f is independently hydrogen or C 1-3 alkyl; R 3 is hydrogen or C 1-6 alkyl, each optionally substituted with one to two C 1-6 alkoxy or oxo, or a pharmaceutically acceptable salt thereof. 8. Spoj prema zahtjevu 7, naznačen time, da Prsten G je ciklopropil; Ra je -F ili -Cl, metil, metilsulfonil ili cijano; Rb je -CH3, karboksil, -F, -Cl, -Br, -I, -CF3, ciklopropil, -OCH3, -CO2Me, -NRcRd, -(CH2)-NRcRd, R3-S(O)m-, R3-S(O)2-NRe-, R3-NRe-S(O)2-, -NRf-C(O)-Re, -C(O)NRcRd ili morfolinil; svaki Rc, Rd je neovisno vodik, -CH3, -C(O)CH3, -CH2CN, C1-4 alkoksikarbonil, metoksikarbonil-C1-2 alkil-, metoksikarbonil-C3cikloalkil- ili -(CH2)-C(O)-NReRf; svaki Re, Rf je neovisno vodik ili -CH3; R3 je vodik ili C1-4 alkil, svaki opcijski supstituiran s jednim do dva -OCH3 ili okso, ili njegova farmaceutski prihvatljiva sol.8. Compound according to claim 7, characterized in that Ring G is cyclopropyl; Ra is -F or -Cl, methyl, methylsulfonyl or cyano; Rb is -CH3, carboxyl, -F, -Cl, -Br, -I, -CF3, cyclopropyl, -OCH3, -CO2Me, -NRcRd, -(CH2)-NRcRd, R3-S(O)m-, R3 -S(O)2-NRe-, R3-NRe-S(O)2-, -NRf-C(O)-Re, -C(O)NRcRd or morpholinyl; each Rc, Rd is independently hydrogen, -CH3, -C(O)CH3, -CH2CN, C1-4 alkoxycarbonyl, methoxycarbonyl-C1-2 alkyl-, methoxycarbonyl-C3cycloalkyl- or -(CH2)-C(O)-NReRf ; each R e , R f is independently hydrogen or -CH 3 ; R 3 is hydrogen or C 1-4 alkyl, each optionally substituted with one to two -OCH 3 or oxo, or a pharmaceutically acceptable salt thereof. 9. Spoj prema bilo kojem od zahtjeva 1, 2 i 6, naznačen time, da Prsten G je ciklopropil ili ciklobutil; ili njegova farmaceutski prihvatljiva sol.9. A compound according to any one of claims 1, 2 and 6, characterized in that Ring G is cyclopropyl or cyclobutyl; or a pharmaceutically acceptable salt thereof. 10. Spoj prema bilo kojem od zahtjeva 1, 3, 4, 6 i 7, naznačen time, da Rc je vodik ili C1-6 alkil, i Rd je C1-6 acil, cijano-C1-6 alkil-, C1-6 alkoksikarbonil-C0-3 alkil-, C1-6 alkoksikarbonil-C3-10 cikloalkil ili -(CH2)n-C(O)-NReRf; svaki Re, Rf je neovisno vodik, C1-6 alkil, ili njegova farmaceutski prihvatljiva sol.10. Compound according to any one of claims 1, 3, 4, 6 and 7, characterized in that R c is hydrogen or C 1-6 alkyl, and Rd is C1-6 acyl, cyano-C1-6 alkyl-, C1-6 alkoxycarbonyl-C0-3 alkyl-, C1-6 alkoxycarbonyl-C3-10 cycloalkyl or -(CH2)n-C(O)-NReRf; each Re, Rf is independently hydrogen, C1-6 alkyl, or a pharmaceutically acceptable salt thereof. 11. Spoj prema bilo kojem od zahtjeva 1, 3, 4, 6 i 7, naznačen time, da Ar2 je fenil, pirimidinil, furanil, tiazolil ili piridil, svaki opcijski supstituiran s jednim do dva Rb; Rb je -SO2Me, -I, -Br, -Cl, -CF3, -OMe, -NMe2, -CONHMe, -SO2NH2, ili njegova farmaceutski prihvatljiva sol.11. A compound according to any one of claims 1, 3, 4, 6 and 7, characterized in that Ar 2 is phenyl, pyrimidinyl, furanyl, thiazolyl or pyridyl, each optionally substituted with one to two Rb; Rb is -SO2Me, -I, -Br, -Cl, -CF3, -OMe, -NMe2, -CONHMe, -SO2NH2, or a pharmaceutically acceptable salt thereof. 12. Spoj prema zahtjevu 11, naznačen time, da Ar2 je kako slijedi: [image] ili njegova farmaceutski prihvatljiva sol.12. Compound according to claim 11, characterized in that Ar2 is as follows: [image] or a pharmaceutically acceptable salt thereof. 13. Spoj prema bilo kojem od zahtjeva 1 do 3 i 6, naznačen time, da Rg je i) C1-2 alkil, -CF3, C2 alkenil, fenil, C1-4 alkoksi, karbociklil-CH2O-, karbociklil-CH2-, -CH2OH, hidroksil, -CO2C1-4 alkil ili okso; ili ii) metil, vinil, -CF3, fenil, -CH2OH ili hidroksil; ili njegova farmaceutski prihvatljiva sol.13. A compound according to any one of claims 1 to 3 and 6, characterized in that Rg is i) C1-2 alkyl, -CF3, C2 alkenyl, phenyl, C1-4 alkoxy, carbocyclyl-CH2O-, carbocyclyl-CH2-, -CH2OH, hydroxyl, -CO2C1-4 alkyl or oxo; or ii) methyl, vinyl, -CF3, phenyl, -CH2OH or hydroxyl; or a pharmaceutically acceptable salt thereof. 14. Spoj prema zahtjevu 1, naznačen time, da je odabran od sljedećih: [image] [image] [image] [image] [image] [image] [image] [image] ili njegova farmaceutski prihvatljiva sol. 14. The compound according to claim 1, characterized in that it is selected from the following: [image] [image] [image] [image] [image] [image] [image] [image] or a pharmaceutically acceptable salt thereof. 15. Farmaceutski sastav, naznačen time, da obuhvaća farmaceutski učinkovitu količinu spoja prema bilo kojem od zahtjeva 1 do 14 i jedan ili više farmaceutskih nosača i/ili pomoćnih sredstava.15. Pharmaceutical composition, characterized in that it comprises a pharmaceutically effective amount of the compound according to any one of claims 1 to 14 and one or more pharmaceutical carriers and/or auxiliaries. 16. Spojevi prema prema bilo kojem od zahtjeva 1 do 14, naznačeni time, da se upotrebljavaju u liječenju kroničnog zapaljenja, alergija, kontaktnog dermatitisa, psorijaze, reumatoidnog artritisa, multiple skleroze, dijabetesa tipa 1, upalne bolesti crijeva, sindroma Guillain-Barre, Crohnove bolesti, ulcerativnog kolitisa, bolesti zbog reakcije usadka protiv stanice domaćina, Alzheimerove bolesti, astme, kroničnog oboljenja bubrega, sepse, autoimunog miokarditisa i eritematoze sistemskog lupusa. 16. Compounds according to any one of claims 1 to 14, characterized in that they are used in the treatment of chronic inflammation, allergies, contact dermatitis, psoriasis, rheumatoid arthritis, multiple sclerosis, type 1 diabetes, inflammatory bowel disease, Guillain-Barre syndrome, Crohn's disease, ulcerative colitis, disease due to the reaction of the graft against the host cell, Alzheimer's disease, asthma, chronic kidney disease, sepsis, autoimmune myocarditis and systemic lupus erythematosus.
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